scholarly journals Epigenetic Reprogramming of TGF-β Signaling in Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 726 ◽  
Author(s):  
Sudha Suriyamurthy ◽  
David Baker ◽  
Peter ten Dijke ◽  
Prasanna Vasudevan Iyengar
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Mechanisms ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Selective Targeting

The Transforming Growth Factor-β (TGF-β) signaling pathway has a well-documented, context-dependent role in breast cancer development. In normal and premalignant cells, it acts as a tumor suppressor. By contrast, during the malignant phases of breast cancer progression, the TGF-β signaling pathway elicits tumor promoting effects particularly by driving the epithelial to mesenchymal transition (EMT), which enhances tumor cell migration, invasion and ultimately metastasis to distant organs. The molecular and cellular mechanisms that govern this dual capacity are being uncovered at multiple molecular levels. This review will focus on recent advances relating to how epigenetic changes such as acetylation and methylation control the outcome of TGF-β signaling and alter the fate of breast cancer cells. In addition, we will highlight how this knowledge can be further exploited to curb tumorigenesis by selective targeting of the TGF-β signaling pathway.

scholarly journals Transforming Growth Factor β/NR4A1-Inducible Breast Cancer Cell Migration and Epithelial-to-Mesenchymal Transition Is p38α (Mitogen-Activated Protein Kinase 14) Dependent

2017 ◽  
Vol 37 (18) ◽  
Author(s):  
Erik Hedrick ◽  
Stephen Safe
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Growth Factor ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein

ABSTRACT Transforming growth factor β (TGF-β)-induced migration of triple-negative breast cancer (TNBC) cells is dependent on nuclear export of the orphan receptor NR4A1, which plays a role in proteasome-dependent degradation of SMAD7. In this study, we show that TGF-β induces p38α (mitogen-activated protein kinase 14 [MAPK14]), which in turn phosphorylates NR4A1, resulting in nuclear export of the receptor. TGF-β/p38α and NR4A1 also play essential roles in the induction of epithelial-to-mesenchymal transition (EMT) and induction of β-catenin in TNBC cells, and these TGF-β-induced responses and nuclear export of NR4A1 are blocked by NR4A1 antagonists, the p38 inhibitor SB202190, and kinase-dead [p38(KD)] and dominant-negative [p38(DN)] forms of p38α. Inhibition of NR4A1 nuclear export results in nuclear export of TGF-β-induced β-catenin, which then undergoes proteasome-dependent degradation. TGF-β-induced β-catenin also regulates NR4A1 expression through formation of the β-catenin–TCF-3/TCF-4/LEF-1 complex on the NR4A1 promoter. Thus, TGF-β-induced nuclear export of NR4A1 in TNBC cells plays an essential role in cell migration, SMAD7 degradation, EMT, and induction of β-catenin, and all of these pathways are inhibited by bis-indole-derived NR4A1 antagonists that inhibit nuclear export of the receptor and thereby block TGF-β-induced migration and EMT.

scholarly journals Epithelial to Mesenchymal Transition Promotes Breast Cancer Progression via a Fibronectin-dependent STAT3 Signaling Pathway

2013 ◽  
Vol 288 (25) ◽  
pp. 17954-17967 ◽  
Author(s):  
Nikolas Balanis ◽  
Michael K. Wendt ◽  
Barbara J. Schiemann ◽  
Zhenghe Wang ◽  
William P. Schiemann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Cancer Progression ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

scholarly journals TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion

2014 ◽  
Vol 25 (22) ◽  
pp. 3528-3540 ◽  
Author(s):  
Lukas D. Osborne ◽  
George Z. Li ◽  
Tam How ◽  
E. Tim O'Brien ◽  
Gerard C. Blobe ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Cell Mechanics ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Stiffness ◽  
Nucleotide Exchange ◽  
Functional Connection ◽  
Mesenchymal Transition ◽  
Invasion Capacity

Recent studies implicate a role for cell mechanics in cancer progression. The epithelial-to-mesenchymal transition (EMT) regulates the detachment of cancer cells from the epithelium and facilitates their invasion into stromal tissue. Although classic EMT hallmarks include loss of cell–cell adhesions, morphology changes, and increased invasion capacity, little is known about the associated mechanical changes. Previously, force application on integrins has been shown to initiate cytoskeletal rearrangements that result in increased cell stiffness and a stiffening response. Here we demonstrate that transforming growth factor β (TGF-β)–induced EMT results in decreased stiffness and loss of the normal stiffening response to force applied on integrins. We find that suppression of the RhoA guanine nucleotide exchange factors (GEFs) LARG and GEF-H1 through TGF-β/ALK5–enhanced proteasomal degradation mediates these changes in cell mechanics and affects EMT-associated invasion. Taken together, our results reveal a functional connection between attenuated stiffness and stiffening response and the increased invasion capacity acquired after TGF-β–induced EMT.

scholarly journals Cell size and invasion in TGF-β–induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway

2007 ◽  
Vol 178 (3) ◽  
pp. 437-451 ◽  
Author(s):  
Samy Lamouille ◽  
Rik Derynck
Keyword(s):  
Cell Size ◽  
Cancer Progression ◽  
Translational Regulation ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mammalian Target Of Rapamycin ◽  
Specific Inhibitor ◽  
Transforming Growth Factor Β ◽  
Initiation Factor ◽  
Mesenchymal Transition

Epithelial to mesenchymal transition (EMT) occurs during development and cancer progression to metastasis and results in enhanced cell motility and invasion. Transforming growth factor-β (TGF-β) induces EMT through Smads, leading to transcriptional regulation, and through non-Smad pathways. We observe that TGF-β induces increased cell size and protein content during EMT. This translational regulation results from activation by TGF-β of mammalian target of rapamycin (mTOR) through phosphatidylinositol 3-kinase and Akt, leading to the phosphorylation of S6 kinase 1 and eukaryotic initiation factor 4E–binding protein 1, which are direct regulators of translation initiation. Rapamycin, a specific inhibitor of mTOR complex 1, inhibits the TGF-β–induced translation pathway and increase in cell size without affecting the EMT phenotype. Additionally, rapamycin decreases the migratory and invasive behavior of cells that accompany TGF-β–induced EMT. The TGF-β–induced translation pathway through mTOR complements the transcription pathway through Smads. Activation of mTOR by TGF-β, which leads to increased cell size and invasion, adds to the role of TGF-β–induced EMT in cancer progression and may represent a therapeutic opportunity for rapamycin analogues in cancer.

scholarly journals Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 183
Author(s):  
Akshita B. Bhatt ◽  
Saloni Patel ◽  
Margarite D. Matossian ◽  
Deniz A. Ucar ◽  
Lucio Miele ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and β-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.

scholarly journals The Importance of Controlling the TGF-β Signaling Pathway in the Gastric Cancer Microenvironment

2017 ◽  
Author(s):  
Jun Kinoshita ◽  
Sachio Fushida ◽  
Tetsuo Ohta
Keyword(s):  
Gastric Cancer ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Stromal Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Clinical Settings ◽  
Mesenchymal Transition ◽  
Tumor Growth And Metastasis ◽  
Carcinoma Associated Fibroblasts

Gastric cancer is an intractable disease with a high incidence of peritoneal dissemination and obstructive symptoms (e.g. ileus, jaundice, and hydronephrosis) arising from accompanying marked fibrosis. Microenvironmental interactions between cancer cells and stromal cells are the suggested cause of the disease. Transforming growth factor (TGF-β) is an intriguing cytokine exhibiting dual roles in malignant disease, acting as an important mediator of cancer invasion, metastasis, and angiogenesis as well as exhibiting antitumor functions. Moreover, the TGF-β pathway contributes to the generation of a favorable microenvironment for tumor growth and metastasis throughout the steps of carcinogenesis. Among these effects, TGF-β induces the epithelial-to-mesenchymal transition with prometastatic functions, contributes to the conversion of stromal cells to carcinoma-associated fibroblasts, and suppresses the function of immune cells, which compromises the antitumor immune response, leading to cancer progression and stromal fibrosis. In this review, we address the role of the essential TGF-β signaling pathway in the regulation of the activities of components of the tumor microenvironment of gastric cancer and how this contributes to tumor progression and stromal fibrosis. We then explore the potential to optimize therapy that inhibits TGF-β signaling in the preclinical and clinical settings of gastric cancer.

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